p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint

A recently identified ribonucleotide reductase (RR), p53R2, is directly reg ulated by p53 for supplying nucleotides to repair damaged DNA. We examined the role of this p53R2-dependent pathway for DNA synthesis in a p53-regulat ed cell cycle checkpoint, comparing it to R2-dependent DNA synthesis. The e levation of DNA synthesis activity through RR in response to gamma -irradia tion was closely correlated with the level of expression of p53R2 but not o f R2. The p53R2 product accumulated in nuclei, whereas R2 levels in cytopla sm decreased. We found a point mutation of p53R2 in cancer cell line HCT116 , which resulted in loss of RR activity. In those cells, DNA damage-inducib le apoptotic cell death was enhanced through transcriptional activation of p53AIP1. The results suggest that p53R2-dependent DNA synthesis plays a piv otal role in cell survival by repairing damaged DNA in the nucleus and that dysfunction of this pathway might result in activation of p53-dependent ap optosis to eliminate dangerous cells.